In animals and humans, stress and corticosteroid excess are associated with changes in hippocampal structure and functioning. These findings may have important implications to patients with mood disorders, as a subset of people with major depressive disorder and bipolar disorder show evidence of HPA axis activation. In animals, hippocampal changes secondary to corticosteroids can be attenuated with agents that modulate excitatory amino acids. Histological changes can be prevented and reversed with phenytoin, a glutamate release inhibitor (e.g. phenytoin), or an N-methyl-D-aspartate (NMDA) receptor antagonist. Our group has developed a research program, in part funded through a K award from NIMH, using patients in medical settings receiving prescription corticosteroid (e.g. prednisone) therapy as a model system to explore the effects of cortisol elevations on the human brain. In prior studies we documented primarily manic symptomatology during acute exposure to high doses of prednisone, primarily depressive symptomatology during chronic exposure to lower dosages of prednisone, deficits in declarative memory, changes in N-acetyl aspartate (a marker of neuronal viability), and reduction in hippocampal volume in prednisone-treated patients. We conducted a randomized, controlled trial of phenytoin in asthma patients receiving prednisone and found evidence of improvement in mood but not memory with phenytoin compared to placebo. In this application we propose examining the potential neuroprotective properties of phenytoin in humans receiving corticosteroids using a different experimental design than in our prior study. We propose to examine whether phenytoin can attenuate the effects of corticosteroids on the human hippocampus using functional magnetic resonance imaging (fMRI) in a group of 16 healthy controls who will receive hydrocortisone, phenytoin, and both medications together in randomized, double-blind, placebo-controlled pilot study using a within-subject crossover design. Based on data in the literature and our own pilot data we hypothesize that hydrocortisone exposure will decrease task-related hippocampal activation and phenytoin given concurrently with hydrocortisone will attenuate this reduction in activation. As secondary aims, mood and cognition will be assessed. We have assembled a research team with expertise in neuroimaging, neuropsychology, statistics, endocrinology, seizure medications, and the neuroendocrine system to conduct the study. The findings will have implications for patients with major depressive disorder and the millions of people treated each year with prescription corticosteroids. The study is designed as a pilot project. If the results are promising a larger, definitive study will be submitted later as an R01 application. In addition, we will use this basic design in future studies to test potential neuroprotective medications other than phenytoin. The study will use neuroimaging to determine the effects of cortisol, a stress hormone, on the human brain. The study will determine if phenytoin, a medication used for seizures, protects the human brain from the adverse effects of cortisol. [unreadable] [unreadable] [unreadable] [unreadable]